Herpes simplex virus type 1 (HSV-1) infections are a major health problem because they establish a persistent (latent) infection, and recur in response to a variety of endogenous or external stimuli. The long-term goal of these studies is to delineate the rate- limiting component (receptor?) that is responsible for triggering the reactivation of latent HSV-1 and the recurrence of ocular herptic disease, and to characterize this mechanism pharmacologically, so that a means of inhibiting or blocking this reactivation can be developed. Thses basic studies involving induction of virus shedding and recurrent epithelial disease will continue in two previously developed rabbit models: 1) ocular iontophoresis of adrenergic agents, and 2) production of adrenergic agonists and antagonists will be used to define the induction of ocular HSV-1 reactivation. Following reactivation of latent HSV, recurrent herpetic epithelial lesions will be detected and quantified by slit lamp examination. The role of corneal innervation in relation to recurrent ocular reactivation will be studied. Immunohistochemistry and in situ hybridization will be used to assess latently infected neural tissues for herpes specific RNAs and proteins. These results will be used to identify speific subsets of cell bodies in neural tissues that harbor latent HSV. Anatomic localization of the herpes macromolecules in these cell bodies, latently infected with varous HSV strains, will be correlated with the HSV strain pathogenesis and ability to be reazctivated. These studies will be aided by the discorvery that HSV-1 strain CGA-3 can establish and maintain latency but cannot be reactivated in vivo. Development of a non-human primate (squirrel monkey) model will continue. Recent preliminary evidence has shown that inour primate model, ocular HSV-1 latency and recurrences can be demonstrated. Such a model is critically important to verify that the triggers for reactivation of herpes in the primate are the same as those in the rabbit. Recurrent ocular herpes casues extensive ophthalmic problems, some leading to blindness. Currently, no treatment prevents recurrence of this disease. If the trigger that causes the reactivation of latent herpes virus can be identified, a therapeutic strategy, perhaps a specific blocker, can be formulated to inhibit the reactivation of HSV-1 and block recurrent herpetic ocular disease.